The present invention relates to processes for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one (CAS 30071-93-3) which is useful as an intermediate in the preparation of therapeutic agents. In particular, the present invention provides a process for the preparation of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The general processes disclosed in the art for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one result in relatively low and inconsistent yields of the desired product. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one in relatively high yield and with a lower degree of exothermicity and, hence, a greater degree of safety.
It will be appreciated that 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one via a very simple, short and highly efficient synthesis.
The novel process of this invention involves the synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula: 
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiatric disorders, and emesis.
The present invention is directed to processes for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula: 
An embodiment of the general process for the preparation of 3,5-bis(trifluoromethyl)-benzoic acid is as follows: 
wherein:
X is selected from chloro, bromo and iodo; and
R is C1-8alkyl.
In accordance with the present invention, the treatment of acetic anhydride with the Grignard reagent prepared by an exchange reaction between 3,5-bis(trifluoromethyl)bromobenzene and a C1-8 alkyl magnesium halide provides 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one in higher yields and in a safer, more efficient route than the processes disclosed in the art.
In the present invention, C1-8 as in C1-8alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that C1-8alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. In the present invention halo or halide is intended to include chloro, bromo and iodo.
In a preferred embodiment, the present invention is directed to a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one which comprises the exchange reaction of 3,5-bis(trifluoromethyl)bromobenzene with a C1-8alkyl magnesium halide in THF to form a Grignard reagent followed by addition of the Grignard reagent to acetic anhydride to give 1-(3,5-bis(trifluoromethyl)phenyl)-ethan-1-one.
Another embodiment of the present invention is directed to a process for the preparation of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one which comprises the reaction of 3,5-bis(trifluoromethyl)bromobenzene with ethyl magnesium bromide in tetrahydrofuran to form 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide followed by addition of the Grignard reagent to an excess of acetic anhydride to give 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one.
A specific embodiment of the present invention concerns a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide of the formula: 
which comprises:
treating 3,5-bis(trifluoromethyl)bromobenzene of the formula: 
with a Grignard reagent selected from:
ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, in an organic solvent to form 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide.
Another specific embodiment of the present invention concerns a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide of the formula: 
which comprises:
treating 3,5-bis(trifluoromethyl)bromobenzene of the formula: 
with ethyl magnesium bromide or isopropyl magnesium chloride in an organic solvent to form 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide.
Another specific embodiment of the present invention concerns a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula: 
which comprises:
a) treating 3,5-bis(trifluoromethyl)benzene of the formula: 
with a Grignard reagent selected from:
ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, in an organic solvent to form a Grignard reagent of the formula: 
b) followed by contacting the Grignard reagent with acetic anhydride in an organic solvent to give 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula: 
Another specific embodiment of the present invention concerns a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula: 
which comprises:
a) treating 3,5-bis(trifluoromethyl)benzene of the formula: 
with a Grignard reagent selected from: ethyl magnesium bromide and isopropyl magnesium chloride, in an organic solvent to form a Grignard reagent of the formula: 
b) followed by contacting the Grignard reagent with acetic anhydride in an organic solvent to give 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula: 
In the present invention it is preferred that the Grignard reagent is added to the acetic anhydride.
In a more preferred embodiment, following step (b) excess acetic anhydride is removed by the addition of an aqeueous solution of a base, such as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, and the like.
Preferred solvents for conducting the instant process comprise an organic solvent which is selected from toluene, tetrahydrofuran (G), diethyl ether, diglyme, and methyl t-butyl ether. The most preferred organic solvent is tetrahydrofuran. In the formation of the Grignard reagent, tetrahydrofuran or diethyl ether are the more preferred organic solvents and tetrahydrofuran is the most preferred organic solvent.
The C1-8 alkyl magnesium halide is preferably selected from ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, more preferably selected from ethyl magnesium bromide and isopropyl magnesium chloride, and even more preferably ethyl magnesium bromide. The magnesium employed to prepare the alkyl Grignard reagent may be in the form of magnesium granules, magnseium turnings, magnesium dust, magnesium powder, suspension of magnesium in oil, and the like. To mimimize safety risks, the use of magnesium granules is preferred.
Formation of the Grignard of 1-(3,5-bis(trifluoromethyl)phenyl)-bromide may be performed in tetrahydrofuran at between about 30 and 35xc2x0 C. The reaction is exothermic and the reaction may be controlled by the rate of addition of the bromide to the magnesium slurry. The reaction mixture may be aged at reflux until  less than 1 mol % of bromide remains. Grignard formation is usually complete within 2 hours, however reaction times of up to 5 hours give comparable yields of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one.
Alternatively, to minimize solvent loss, the Grignard formation may be performed in tetrahydrofuran at a temperature range between about 0 and 20xc2x0 C., and preferably a reaction temperature range between about 0 and 10xc2x0 C.
In the present invention, it is preferred that the Grignard reagent be added to the acetic anhydride. In the present invention, it is also preferred that an excess of acetic anhydride be present when reacting the Grignard reagent. In the present invention, it is more preferred that the Grignard reagent be added to an excess of acetic anhydride.
Surprisingly, the presence of an excess of acetic anhydride (i.e. greater than a 1:1 molar ratio) is important to providing high yields of the desired product. When the acetic anhydride was added to the Grignard reagent at 20xc2x0 C. an exothermic reaction resulted which produced a bis-adduct of the formula: 
Surprisingly, however, when the Grignard reagent was added to acetic anhydride, little byproduct was formed and 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one was obtained in 85-90% yield.
In the present invention, it is preferred that the Grignard reagent is added to cooled acetic anhydride. In the present invention, it is more preferred that the Grignard reagent is added slowly (over a period of 1-2 hr, for example) to a cooled mixture of acetic anhydride in either tetrahydrofuran or tert-butyl methylether, maintaining the temperature at below about 5xc2x0 C., or alternatively between about xe2x88x9210 to xe2x88x9215xc2x0 C.
In the addition of the Grignard reagent with acetic anhydride, it is preferred that the temperature of the acetic anhydride upon addition of the Grignard reagent be less than about 5xc2x0 C., more preferrably, less than about xe2x88x9210xc2x0 C., it is even more preferrably less than about xe2x88x9215xc2x0 C. Upon addition of the Grignard reagent, the temperature of the reaction mixture may be raised to about 5xc2x0 C.
In a preferred additional embodiment, isolation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one may be achieved by adding cold water to the reaction mixture followed by the slow addition of aqueous solution of a base to hydrolyze the excess acetic anhydride. The base may be an inorganic base selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, and the like. A preferred base is sodium hydroxide. The pH of the aqueous layer is preferably brought to greater than 10. When the pH is greater than 10, the mixture is extracted with tert-butyl methylether. The extracts are washed with aqueous sodium bicarbonate and aqueous sodium chloride and the solvents are removed by distillation.
The 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one obtained in accordance with the present invention may be used as starting material in further reactions directly or following distillation. The isolated product can be distilled at atmospheric or reduced pressure to provide a clear colorless oil with BP=185-189xc2x0 C.
Many of the starting materials are either commercially available or known in the literature and others can be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.